PROJECT SUMMARY/ABSTRACT Working memory is the ability to hold items ?in mind?. It is at the core of cognition, providing the workspace for complex behaviors. However, despite its critical nature, working memory is surprisingly limited: holding 3-4 items at a time. To compensate for this limited capacity, working memory is dynamically controlled: access to working memory is tightly regulated and representations in working memory are selectively manipulated. Disrupting one?s ability to control working memory can be pathological; such disruptions are believed to be a core cognitive deficit in schizophrenia1 and may underlie intrusive thoughts in anxiety2 and depression3. To develop novel, mechanistically-informed, treatments for these diseases, we must first develop a detailed understanding of the neural mechanisms that control working memory. We propose to investigate three ways in which working memory is controlled: First, one must be able to control access to working memory. A ?gating? signal is thought to provide this control: to-be-remembered stimuli are gated into memory; to-be-ignored stimuli are not. Our first aim will distinguish hypotheses on the source of this gating signal; we will leverage our novel many-electrode recording techniques in non-human primates to test how interactions between prefrontal cortex and basal ganglia gate representations into memory. In addition, we will test the prediction that gating changes the temporal dynamics of sensory representations in order to maintain them in memory. Second, once a set of items are in working memory, one must be able to select a specific item in order to use it to guide behavior. This process is akin to attention, which selects specific external stimuli. Our second aim will use our many-electrode recording techniques to a) discover the neural mechanisms that control selection from working memory and b) test hypotheses that relate these mechanisms to those that control attention. Third, when remembering multiple stimuli, one must judiciously allocate the limited resource of working memory amongst them: stimuli with greater behavioral relevance should be more accurately remembered. Our third aim will determine how neurons in prefrontal and parietal cortex control the prioritization of items in working memory and how this prioritization impacts working memory representations throughout prefrontal, parietal, and sensory cortices. While our proposed research is basic in nature, we believe it is an important first step in a mechanistic understanding of the core cognitive deficits of several mental illnesses, including schizophrenia and anxiety. Our hope is that this understanding will improve mental health by leading to new diagnostics and treatments for cognitive disorders. In particular, we hope to use our results to develop physiological markers that will improve detection, allow for earlier intervention, and guide targeted treatments. Our long-term goal is to develop a cognitive prosthetic that combines electrophysiology and stimulation to treat neuropsychiatric diseases.